Distinct Patterns of IFITM-Mediated Restriction of Filoviruses, SARS Coronavirus, and Influenza A Virus

Abstract

Interferon-inducible transmembrane proteins 1, 2, and 3 (IFITM1, 2, and 3) are recently identified viral restriction factors that inhibit infection mediated by the influenza A virus (IAV) hemagglutinin (HA) protein. Here we show that IFITM proteins restricted infection mediated by the entry glycoproteins (GP1,2) of Marburg and Ebola filoviruses (MARV, EBOV). Consistent with these observations, interferon-β specifically restricted filovirus and IAV entry processes. IFITM proteins also inhibited replication of infectious MARV and EBOV. We observed distinct patterns of IFITM-mediated restriction: compared with IAV, the entry processes of MARV and EBOV were less restricted by IFITM3, but more restricted by IFITM1. Moreover, murine Ifitm5 and 6 did not restrict IAV, but efficiently inhibited filovirus entry. We further demonstrate that replication of infectious SARS coronavirus (SARS-CoV) and entry mediated by the SARS-CoV spike (S) protein are restricted by IFITM proteins. The profile of IFITM-mediated restriction of SARS-CoV was more similar to that of filoviruses than to IAV. Trypsin treatment of receptor-associated SARS-CoV pseudovirions, which bypasses their dependence on lysosomal cathepsin L, also bypassed IFITM-mediated restriction. However, IFITM proteins did not reduce cellular cathepsin activity or limit access of virions to acidic intracellular compartments. Our data indicate that IFITM-mediated restriction is localized to a late stage in the endocytic pathway. They further show that IFITM proteins differentially restrict the entry of a broad range of enveloped viruses, and modulate cellular tropism independently of viral receptor expression.

Human respiratory syncytial virus infection is inhibited by IFN-induced transmembrane proteins

“…Compared with other viruses inhibited by IFITM proteins, the restriction of RSV was more profound than for human immunodeficiency virus, hepatitis C virus and influenza virus A at the same m.o.i. (Huang et al, 2011;Lu et al, 2011;Raychoudhuri et al, 2011). However, Rift Valley fever virus infection also displayed intensive inhibition by IFITM3 (Mudhasani et al, 2013).…”

“…However, IFITM1 restricted HIV replication without affecting viral entry (Lu et al, 2011). Recent studies indicated that IFITM3 localized to endosomes and lysosomes, leading to alterations in the endosomal compartments, including increased association with clathrin -an important protein utilized by multiple viruses during virus endocytosis (Huang et al, 2011;Yount et al, 2012). However, another report contradicted the results of clathrin-mediated endocytosis of RSV and demonstrated that RSV utilized an actin-dependent, clathrin-and pH-independent macropinocytosis process to enter cells (Krzyzaniak et al, 2013).…”

“…Recently, one family of ISGs, called IFN-inducible transmembrane (IFITM) proteins, and known to play diverse roles in cell signalling, adhesion, tumour genesis and immune regulation, was found to have the ability to restrict the cell entry and replication of a number of viruses. Most of the viruses restricted by the IFITM proteins are enveloped viruses, such as influenza A, dengue virus and West Nile virus (Brass et al, 2009;Weidner et al, 2010;Huang et al, 2011;Lu et al, 2011;Raychoudhuri et al, 2011;Mudhasani et al, 2013), but reovirus, which is a non-enveloped dsRNA virus, was also recently reported to be sensitive to IFITM3 repression (Anafu et al, 2013). IFITM3 has been reported to restrict cell infection of RSV and control disease pathogenesis in the Ifitm3 knockout mouse model (Everitt et al, 2013).…”

Identification of the Polymorphisms in IFITM2 and IFITM5 Genes and their Association with Ulcerative Colitis

“…Ulcerative colitis (UC) and crohn's disease (CD) in humans are the two major forms of IBD [10]. IBDs are complex and multifactorial involving genetic, environmental and microbial factors [1,13,1]. Cytokine production in lamina propria CD4 + T lymphocytes differs between CD and UC.…”

Les IFITM, un obstacle commun à de nombreux virus

“…C'est lors d'un vaste crible d'ARNi (ARN interférents) qu'en 2009, l'équipe du Dr Elledge a identifié une nouvelle famille de facteurs de restriction, les IFITM (interferon induced transmembrane proteins), actifs sur le virus de la grippe, mais aussi celui de la dengue, du Nile occidental et de la fièvre jaune [10]. Par la suite, plusieurs équipes ont cherché à déterminer le spectre d'activité antivirale de ces protéines, et il est apparu qu'un très grand nombre de virus étaient inhibés par les IFITM (Tableau I) [10][11][12][13][14][15][16][17][18][19]. Ainsi, les IFITM sont capables d'inhiber plusieurs virus à ARN, indépendamment de la polarité de leur génome 1 .…”